123I-mIBG assessed cardiac sympathetic activity: standardizing towards clinical
implementation
Verschure, D.O.
Publication date
2017
Document Version
Other version
License
Other
Link to publication
Citation for published version (APA):
Verschure, D. O. (2017). 123I-mIBG assessed cardiac sympathetic activity: standardizing
towards clinical implementation.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)
and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open
content license (like Creative Commons).
Renal function in relation to
cardiac
123
I-mIBG
scintigraphy in
patients with chronic heart failure
DO Verschure GA Somsen BL van Eck-Smit HJ Verberne
ABSTRACT
AimThe aim of this study was to explore if estimates of renal function could explain variability of
123I-meta-iodobenzylguanidine (123I-mIBG) assessed myocardial sympathetic activity. Furthermore
estimates of renal function were compared to 123I-mIBG as predictors of cardiac death in chronic
heart failure (CHF). Materials and method
Semi-quantitative parameters of 123I-mIBG myocardial uptake and washout (WO) were calculated
using early and late heart/mediastinum (H/M) ratio and 123I-mIBG WO. Renal function was
calculated as estimated Creatinine Clearance (e-CC) and as estimated Glomerular Filtration Rate (e-GFR).
Results
Thirty-nine patients with CHF (24 males; age: 64.4 ± 10.5 years; NYHA II/III/IV: 17/20/2; LVEF: 24.0 ± 11.5%) were studied. Variability in any of the semi-quantitative 123I-mIBG myocardial parameters
could not be explained by e-CC or e-GFR. During follow-up (60 ± 37 months) there were 6 cardiac deaths. Cox proportional hazard regression analysis showed that late H/M ratio was the only independent predictor for cardiac death (Chi-square 3.2, regression coefficient: −4.095; standard error: 2.063; hazard ratio: 0.17 [95% CI: 0.000 – 0.950]). Addition of estimates of renal function did not significantly change the Chi-square of the model.
Conclusion
Semi-quantitative 123I-mIBG myocardial parameters are independent of estimates of renal
function. In addition, cardiac sympathetic innervation assessed by 123I-mIBG scintigraphy seems
7
INTRODUCTION
The myocardial sympathetic nervous system is activated in patients with chronic heart failure (CHF) and has been shown to be associated with increased mortality. Cardiac sympathetic innervation can be scintigraphically visualized by 123
I-meta-iodobenzylguanidine (123I-mIBG), a radiolabelled analog of noradrenalin and has been
shown to be a powerful prognostic marker in patients with CHF.1,2 In addition to 123I-mIBG
there are many other prognostic markers in patients with CHF. Estimates of renal function for example, as measured by creatinine clearance and glomerular filtration rate (GFR), have been associated with mortality and morbidity in CHF.3-5 Interestingly in patients with
chronic renal failure myocardial washout (WO) of 123I-mIBG, as a measure of increased
myocardial sympathetic activity, has been shown to be increased.6 However, there
is limited data on a direct comparison of the respective prognostic predictive value of sympathetic hyperactivity and renal dysfunction.7 Major clinical trials aimed to assess the
prognostic value of 123I-mIBG have often excluded patients with substantial renal failure,
further limiting the amount of prognostic information comparing these two variables.2
Furthermore, there are complex interactions between sympathetic regulation of renal function and cardiac function. For example increased sympathetic activity reduces the renal filtration fraction8,9 and a reduced GFR is associated with a reduced blood
clearance of 123I-mIBG.10 In a recent study it was shown that differences in the rate
of renal excretion did not contribute to variability in the mediastinal and myocardial
123I-mIBG uptake.11 However, whether this reduced blood clearance of 123I-mIBG has
any impact on the semi-quantitative myocardial parameters is unknown. Therefore, the purpose of this study was twofold: 1) to explore if estimates of renal function could explain variability of 123I-mIBG assessed myocardial sympathetic activity and 2) to
compare the prognostic value of estimates of renal function and myocardial 123I-mIBG
assessed myocardial sympathetic activity in patients with CHF.
MATERIAL AND METHODS
The study was designed to re-evaluate the results of 123I-mIBG imaging studies and
renal function in patients with CHF prior to 1st of November 2006 in relation to cardiac events. Requirements for inclusion of subjects in this “retrospective” study were: availability of the original digital 123I-mIBG image files; availability of serum creatinine
measurements within 1 month before 123I-mIBG scintigraphy. Between January 1, 1996
and October 31, 2006, 39 CHF patients visiting the outpatient heart failure clinic met these requirements. Renal function was estimated using the serum creatinine based Cockcroft-Gault equation (estimated Creatinine Clearance: e-CC) and the abbreviated
MDRD equation (estimated Glomerular Filtration Rate: e-GFR).12,13 Dutch national law
does not require local ethics committee approval for retrospective studies. The study complies with the Declaration of Helsinki.
CHF severity was clinically evaluated according to the New York Heart Association (NYHA) classification at the time of imaging. The census date for follow-up was set at the 1st of November 2008 (at least 24 months follow-up). The mean follow-up after
123I-mIBG scintigraphy was 60.1 ± 37.2 months (range 1 – 149 months). Measurement of serum creatinine
Serum concentrations of creatinine were determined according to routine hospital procedure. Reference levels for creatinine were 75-110 µmol/L for men and 65-95 µmol/L for women, respectively.
Renal function
Renal function was determined by e-CC using the Cockcroft-Gault equation and expressed as mL/min:
The e-GFR was calculated using the abbreviated MDRD equation:
e-GFR was expressed per 1.73 m2 of body surface area (mL/min/1.73 m2). According to
the guidelines for identification, management and referral of adults with chronic kidney disease, patients were stratified to an impaired kidney function (e-CC or e-GFR < 60 mL/min(/1.73 m2)) and those with a normal e-CC or e-GFR (i.e. ≥ 60 mL/min/1.73 m2).14 123I-mIBG: acquisition and semi-quantitative analysis
Patients underwent myocardial scintigraphy to determine 123I-mIBG uptake reflecting
neural norepinephrine reuptake and retention. To block thyroid uptake of free 123I, all
patients received 100 mg potassium iodide orally, one hour prior to the injection of
123I-mIBG. After a subsequent resting period of at least 30 minutes, patients were
injected intravenously with approximately 185 MBq (5 mCi) of 123I-mIBG (GE Healthcare,
Eindhoven, the Netherlands). Fifteen minutes (early imaging) and 4 h (delayed imaging) after MIBG administration, a 10-min planar anterior image of the thorax was acquired using a dual-head gamma camera (e-cam, Siemens, Hoffman Estate, Illinois, USA). A 20% energy window was centred on the 159 keV photopeak of 123I. Images were
acquired using a medium energy collimator and stored in 128 128 matrix.15
e – CC x (1.04 for females and 1.23 for male)
*
100
ratio
H/M
early
ratio)
H/M
late
ratio
H/M
(early
WO
−
=
[serum creatinine (µmol/L) ] (140 – [age (years)] x [weight (kg)]
e-GFR = 32788 × [serum creatinine (µmol/L)]-1.154 × [age (years)]-0.203
7
An experienced nuclear medicine technologist processed all planar images on a workstation (HERMES Medical Solutions, Stockholm, Sweden). The analysis of the myocardial scintigraphy data was performed blind to clinical status and estimates of renal function. 123I-mIBG myocardial activity was measured using a manually drawn
region of interest (ROI) around the LV. The positioning of the fixed mediastinal ROI was standardized in relation to the lung apex, the lower boundary of the upper mediastinum, and the midline between the lungs.16 To evaluate 123I-mIBG myocardial
uptake the Heart/Mediastinum (H/M) ratio was calculated from the early (early H/M ratio) and delayed images (late H/M ratio). Myocardial 123I-mIBG WO was defined as the
percentage of change in activity from the early and delayed images:
Follow-up
The primary outcome was defined as cardiac death during follow-up (aggregated from: death due to acute pulmonary oedema, progressive heart failure, myocardial infarction or ventricular arrhythmia). The secondary outcome was defined as potentially lethal ventricular arrhythmias during follow-up: documented episode of spontaneous sustained ventricular tachycardia (> 30 s) ventricular tachyarrhythmia, resuscitated cardiac arrest, or appropriate ICD therapy (anti-tachycardia pacing or defibrillation). Long-term follow-up data were obtained from at least one of three sources: visit to the outpatient clinic; review of the patient’s hospital records; personal communication with the patient’s physician. An experienced cardiologist reviewed source documents to confirm occurrence of events. The cardiologist was blinded for both the estimates of renal function and the 123I-mIBG scintigraphic data.
Statistical analysis
Mean values were tested for differences using the unpaired t-test. Linear regression was used to examine the relationship between the estimates of renal function (e-CC and e-GFR) and the 123I-mIBG scintigraphic data (i.e. early H/M ratio, late H/M ratio
and 123I-mIBG WO). The overall goodness-of-fit was expressed as the adjusted R2. The
F-test was used to assess whether the model explained a significant proportion of the variability. A significant adjusted R2 would indicate that variation in the scintigraphically
determined parameters could be explained by a percentage (adjusted R2) of change in
estimates of renal function. Multivariate Cox proportional hazard regression analysis was used to investigate the relation between survival and the following parameters: age, gender, several CHF variables, estimates of renal function and the 123I-mIBG
scintigraphic data. First, several CHF variables (left ventricular ejection fraction (LVEF), NYHA class, QRS duration) and 123I-mIBG semi-quantitative myocardial parameters
WO
(early
H/M
early
ratio
H/M
late
ratio
H/M
ratio)
*
100
WO
−
=
100*
100
ratio
H/M
early
ratio)
H/M
late
ratio
H/M
(early
WO
−
=
*
100
ratio
H/M
early
ratio)
H/M
late
ratio
H/M
(early
WO
−
=
early H/M ratio (early H/M ratio – late H/M ratio)(i.e. early H/M ratio, late H/M ratio and 123I-mIBG WO) were entered into the model
according a stepwise forward likelihood ratio based method. Secondly, the possible additional value of renal function (e-CC and e-GFR) was determined. These data were added to the first model according the enter method (forced addition to the model). Chi-square, Cox proportional hazard regression coefficient (coefficient B) and exponent (exponent B) were used to describe the model and relative contribution of the parameters to the model. Exponent B is the predicted change in hazard for a unit increase in the predictor (i.e. hazard ratio). A p-value < 0.05 was considered to indicate statistical significance. All statistical analyses were performed with SPSS (SPSS for Windows, version 16.0, SPSS Inc, Chicago, Il, USA).
RESULTS
Thirty-nine patients with CHF were included in this study; all patients had stable CHF. Baseline characteristics are described in Table 1. Twenty-three patients (59%) had ischaemia related CHF and sixteen patients had non-ischaemic CHF. Patients with ischaemia related CHF had a lower LVEF compared to those with non-ischaemic CHF (p = 0.034). The majority was male (62%) with a mean age of 64.4 ± 10.5 years. At baseline 94.9% of patients were treated with loop diuretics, 82.1% were on angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), and 46.2% were on beta-blockers.
7
Table 1. Patient characteristics. Overall
(n = 39) Ischaemic (n = 23) Non-ischaemic (n = 16) p-value
Age (years) 64 ± 11 66 ± 10 61 ± 11 0.962 Female/Male 15/24 6/17 7/9 0.057 LVEF (%) 24.0 ± 11.5 20.7 ± 8.6 28.6 ± 13.6 0.034 NYHA class 0.351 II 17 7 8 III 20 11 8 IV 2 2 0 Medical history Myocardial infarction 21 21 0 <0.001 CABG 8 8 0 0.008 PCI 4 4 0 0.078 Hypertension 10 5 5 0.428 Diabetes Mellitus 9 5 4 0.727 Medication Beta-blocker 18 10 8 0.688 ACE-I 29 17 12 0.939 ARB 3 2 1 0.778 CCB 3 2 1 0.778 Amiodarone 13 9 4 0.357 Digoxine 9 4 5 0.312 Loop diuretic 37 22 8 0.791 ECG QRS duration (msec) 163 ± 43 167 ± 36 158 ± 54 0.564 LBBB 32 21 11 0.116 RBBB 1 1 0 0.418 Atrial fibrillation 4 2 2 0.700 NYHA class: New-York Heart association functional classification of heart failure; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; CCB: calcium channel blocker; LVEF: left ventricular ejection fraction; LBBB: left bundle branch block; RBBB: right bundle branch block.
Table 2. Estimates of renal function and 123I-mIBG-derived parameters.
Overall
(n = 39) Ischaemic (n = 23) Non-ischaemic (n = 16) p-value
Renal function e-CC 65.7 ± 33.1 58.1 ± 27.5 78.6 ± 38.6 0.076 e-GFR 60.0 ± 25.5 55.1 ± 26.6 67.1 ± 22.7 0.153 123I-mIBG-derived parameters Early H/M ratio 1.61 ± 0.46 1.51 ± 0.32 1.75 ± 0.58 0.108 Late H/M ratio 1.43 ± 0.38 1.36 ± 0.26 1.54 ± 0.49 0.139 123I-mIBG WO 10.1 ± 10.4 9.21 ± 10.1 11.4 ± 11.0 0.528
e-CC: estimated Creatinine Clearance; e-GFR: estimated Glomerular Filtration Rate; H/M ratio: heart-to-mediastinum ratio; WO: washout. See for other abbreviations Table 1.
Table 3. Normal vs. abnormal estimates of kidney function in relation to 123I-mIBG-derived
parameters.
e-CC <60 mL/min (n = 17) ≥60 mL/min (n = 18) p-value
Early H/M ratio 1.45 ± 0.36 1.74 ± 0.49 0.490
Late H/M ratio 1.29 ± 0.29 1.54 ± 0.41 0.370
123I-mIBG WO 9.9 ± 11.1 10.3 ± 10.0 0.915
e-GFR < 60 mL/min/1.73 m2 (n = 23) ≥ 60 mL/min/1.73 m2 (n = 16) p-value
Early H/M ratio 1.57 ± 0.42 1.67 ± 0.51 0.492
Late H/M ratio 1.38 ± 0.39 1.51 ± 0.36 0.309
123I-mIBG WO 11.2 ± 12.2 8.5 ± 7.0 0.432
7
123I-mIBG and estimates of kidney function
The mean early H/M ratio was 1.61 ± 0.46, the mean late H/M ratio was 1.43 ± 0.38 and the mean 123I-mIBG WO was 10.1 ± 10.4% (Table 2). There was no difference in the 123I-mIBG semi-quantitative parameters or in the e-CC and e-GFR between ischaemic
and non-ischaemic related CHF.
There were 17 patients with an impaired renal function based on e-CC (39.5 ± 10.5 mL/min, range 17-56 mL/min) and 23 with an impaired renal function based on e-GFR (42.0 ± 11.3 mL/min/1.73 m2, range 17-59 mL/min/1.73 m2). Patients with a decreased
e-CC or a decreased e-GFR did not differ in 123I-mIBG semi-quantitative parameters
compared with patients with a normal e-CC or normal e-GFR (Table 3).
The variability in any of the 123I-mIBG semi-quantitative parameters could not be explained
by either e-CC or e-GFR (Table 4). Estimates of renal function could at best explain approximately 3% of the variability of the 123I-mIBG semi-quantitative parameters (p = 0.851). Cardiac death
During follow-up 6 of the 39 (15.4%) patients had a cardiac death; mean interval after
123I-mIBG scintigraphy to cardiac death was 22 months with a range from 4 to 54 months.
All 6 patients died as a result of severe progressive heart failure. Characteristics of patient with cardiac death and survivors are described in Table 5. The cardiac deaths were more likely to have a non-ischaemic aetiology of heart failure (p = 0.022). There was a statistically not significant trend towards lower e-CC and e-GFR values for patients with cardiac death compared to survivors (e-CC 53.4 ± 20.9 vs. 67.8 ± 34.5, p = 0.375; e-GFR 49.1 ± 15.7 vs. 62.0 ± 26.6, p = 0.259, respectively).
Cox proportional hazard regression analysis showed that late H/M ratio was the only independent predictor for cardiac death (Chi-square 3.2, coefficient B: -4.095; standard error: 2.063; hazard ratio: 0.17, 95%CI: 0.000 - 0.950). Forced addition of estimates of renal function did not significantly change the Chi-square of the model (Figure 1A).
Table 4. Variability of the estimates of renal function in relation to 123I-mIBG-derived parameters.
Constant Stand
error c Coefficient b Stand error b Adjusted R
2 p-value
e-CC vs. early H/M ratio 49.3 21.2 10.6 13.1 -0.011 0.428
e-CC vs. late H/M ratio 40.4 24.0 18.2 16.8 0.005 0.285
e-CC vs. 123I-mIBG WO 66.8 8.0 -0.1 0.6 -0.029 0.851
e-GFR vs. early H/M ratio 59.1 15.4 0.6 9.2 -0.027 0.948
e-GFR vs. late H/M ratio 50.4 16.3 6.7 11.0 -0.017 0.546
e-GFR vs. 123I-mIBG WO 64.8 5.7 -0.5 0.4 0.011 0.240
Figure 1. (A) Model predicting cardiac death: late H/M ratio enters the model first (Chi-square =
3.2). The addition of renal function did not significantly change the model (Chi-square for the model including e-CC = 4.1 and for the model including e-GFR = 4.0, respectively). (B) Model predicting potentially lethal arrhythmia: QRS duration is the only significant contributor to the model (Chi-square = 8.5). The addition of renal function did not significantly change the model (Chi-square for the model including e-CC = 8.7 and for the model including e-GFR = 9.1, respectively).
Cardiac death 0 1 2 3 4 5
late H/M e-CC e-GFR
p=0.346
p=0.375
Chi-square
late H/M late H/M
6
Potentially lethal arrhythmia
0 2 4 6 8 10 QRS duration e-CC e-GFR p=0.693 p=0.458 Chi-square QRS duration QRS duration 12
A
B
7
Potentially lethal ventricular arrhythmia
Nine patients developed potentially lethal ventricular arrhythmia: 5 had sustained ventricular tachycardia, 1 patient was resuscitated from a cardiac arrest and 3 patients had an appropriate ICD therapy (i.e. anti-tachycardia pacing). None of these arrhythmias resulted in sudden cardiac death.
Cox proportional hazard regression analysis showed that QRS duration was the only independent predictor for a potentially lethal ventricular arrhythmia (Chi-square 8.5, coefficient B: 0.028; standard error: 0.010; hazard ratio: 1.028, 95%CI: 1.021-1.049). Forced addition of estimates of renal function did not significantly change the Chi-square of the model (Figure 1B). None of the 123I-mIBG semi-quantitative parameters
was predictive for a potentially lethal ventricular arrhythmia.
Table 5. Characteristics of cardiac deaths compared to survivors.
Cardiac Death (n = 6) Survivor (n = 33) p-value
Age (years) 64 ± 14 64 ± 10 0.990 Female/Male 2/4 13/20 0.786 NYHA class 0.529 II 2 15 III 4 16 IV 0 2
Aetiology heart failure
Ischaemic/non-ischaemic 1/5 22/11 0.022 LVEF (%) 20.8 ± 10.9 24.6 ± 11.7 0.467 ECG QRS duration (msec) 175 ± 66 161 ± 38 0.471 LBBB 5 27 0.647 Renal function e-CC 53.4 ± 20.9 67.8 ± 34.5 0.375 e-GFR 49.1 ± 15.7 62.0 ± 26.6 0.259 123I-mIBG-derived parameters Early H/M ratio 1.57 ± 0.36 1.62 ± 0.47 0.839 Late H/M ratio 1.34 ± 0.30 1.45 ± 0.39 0.512 123I-mIBG WO 14.2 ± 12.7 9.4 ± 9.9 0.302
DISCUSSION
Semi-quantitative 123I-mIBG myocardial parameters are independent of estimates of
renal function. In addition, cardiac sympathetic innervation assessed by 123I-mIBG
scintigraphy seems to be superior to renal function in the prediction of prognosis in CHF patients.
Renal function and 123I-mIBG
In subjects with a normal kidney function, intravenous administrated 123I-mIBG
is almost exclusively excreted via the kidneys within 24 hours after injection with approximately 35% of administered 123I-mIBG already excreted by 6 hours.17,18 As a
reduced GFR is associated with a reduced blood clearance of 123I-mIBG, the excretion
of 123I-mIBG is not only dependent on filtration but also by tubular secretion.10 In short
kidney function is essential for the clearance of 123I-mIBG and may therefore influence
scintigraphic outcome. However, the results of our study show that the variability in the semi-quantitative 123I-mIBG myocardial parameters cannot be explained by estimates
of renal function. Therefore within the time-frame of 123I-mIBG cardiac imaging (up
to 4 hours after injection), the semi-quantitative 123I-mIBG myocardial parameters
are independent of renal function. These findings are in line with a recent publication showing that differences in the rate of renal excretion did not contribute to variability in mediastinal and myocardial counts between early and late planar 123I-mIBG images.11
This is eminent for clinical practice as renal dysfunction is often present in CHF patients.19,20
Renal function, 123I-mIBG and prognosis in CHF
Renal dysfunction is not only often present in patients with CHF, the serum creatinine-based estimates of renal function have been shown to be independently related to mortality.21-25 In addition the sympathetic nervous system is one of the neurohormonal
compensation mechanisms that plays an important role in the pathogenesis of CHF. Activation of this cardiac sympathetic system causes down regulation and desensitization of cardiac beta-adrenoreceptors and modification in the post synaptic signal transduction which contributes to arrhythmia development, progression of heart failure and ultimately cardiac death. Our results confirm previous findings that increased cardiac sympathetic activity assessed by 123I-mIBG scintigraphy is related
to mortality.1,2,26
However, there is limited data on a direct comparison of the respective prognostic predictive value of sympathetic innervation and renal dysfunction. To our knowledge only Furuhashi et al. studied this specific subject.7 In patients with CHF and a preserved
7
lacked statistical power to perform Cox proportional hazard regression analysis in the patient group with an impaired renal function (GFR < 60 mL/min/1.73m2).
The lack of additional prognostic value of renal function in our study might be explained by several different but probably interacting factors. First, the aetiology of CHF differs between different studies. In studies with a larger number of patients with ischaemia related cardiomyopathy, a higher predictive value of renal function was found. This might be explained by concomitant peripheral vascular disease and secondary nephrosclerosis. Our patient cohort was not large enough to allow for adequate subgroup analysis and therefore concomitant peripheral vascular disease remains a theoretical explanation for the found discrepancies. Secondly, the differences between our results and the findings of others may be related to the prevalence of reduced kidney function. However, even in patients with increased serum creatinine levels (> 2.5 mg/dl or > 220 μmol/L, approximately 3% of the study population), Opasisch et al. were not able to identify renal function as a prognostic indicator.27 Approximately 47%
of our study population had at least a moderate impairment of renal function (i.e. e-CC or e-GFR < 60 ml/min (/1.73m2)). This prevalence is slightly lower compared to the
majority of published data. Prevalence of renal dysfunction does therefore not explain the absence of renal function as a prognostic indicator.
LIMITATIONS AND CLINICAL IMPLICATIONS
The main limitation of this study is the small number of patients collected over an extended period of time when therapeutic guidelines were changing. This is reflected by the fact that the majority of included patients is relatively undertreated according to the current guidelines.28,29 Furthermore the mortality rate seems to be relatively low (i.e.
15%). However, the mortality rate is in line with the mortality rate as reported by other publications. Furuhashi et al. reported a mortality rate of 11% during a mean follow-up period of 33.7 months7 and the cardiac mortality rate of the ADMIRE-HF study (6%
during a median follow-up period of 17 months).2 The extrapolation of the prognostic
predictive value of our study is probably influenced by these factors. The prognostic findings of our study should therefore be considered as preliminary. However, remains that the aforementioned factors have no impact on the finding that semi-quantitative
CONCLUSION
Semi-quantitative 123I-mIBG myocardial parameters are independent of estimates
of renal function. Although the findings on the prognostic predictive value of this study should be considered as preliminary, the observations suggest that cardiac sympathetic innervation assessed by 123I-mIBG scintigraphy is superior in the
prediction of prognosis in patients with CHF to estimates of renal (dys-) function. This finding might be clinically relevant as creatinine clearance is less costly to assess than
7
REFERENCES
1. Verberne HJ, Brewster LM, Somsen GA, van Eck-Smit BL. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. 2008;29:1147-59.
2. Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010;55:2212-21. 3. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, et al. Renal
function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006; 113: 671-678.
4. Ljungman S, Kjekshus J, Swedberg K. Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial),” Am J Cardiol. 1992;70:479-487.
5. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35:681-689.
6. Kurata C,Wakabayashi Y, Shouda S, OkayamaK, Yamamoto T, Ishikawa A, et al.Enhanced cardiac clearance of iodine-123-MIBG in chronic renal failure. J Nucl Med. 1995;36:2037-43.
7. Furuhashi T, Moroi M. Importance of renal function on prognostic value of cardiac iodine-123 metaiodobenzylguanidine scintigraphy. Ann Nucl Med. 2007;21:57-63. 8. DiBona GF, Kopp UC.Neural control of renal function. Physiol Rev. 1997;77:75-197. 9. Kon V, Yared A, Ichikawa I. Role of renal sympathetic nerves in mediating hypoperfusion
of renal cortical microcirculation in experimental congestive heart failure and acute extracellular fluid volume depletion. J Clin Invest. 1985;76:1913-1920.
10. Blake GM, Lewington VJ, Zivanovic MA, Ackery DM. Glomerular filtration rate and the kinetics of 123I-metaiodobenzylguanidine. Eur J Nucl Med. 1989;15:618-623. 11. Verberne HJ, Verschure DO, Somsen GA, van Eck-Smit BL, Jacobson AF. Vascular
time-activity variation in patients undergoing 123I-MIBG myocardial scintigraphy: implications for quantification of cardiac and mediastinal uptake. Eur J Nucl Med Mol Imag. 2011;38:1132-1138.
12. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976:16:31-41.
13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-470.
14. Tomson C, Blades S,Burden R, et al.Chronic Kidney Disease in Adults. In: UK Guidelines for Identification, Management and Referral. 2009.
15. Verberne HJ, Feenstra C, de Jong WM, Somsen GA, van Eck-Smit BL,E. Busemann Sokole. Influence of collimator choice and simulated clinical conditions on 123I-MIBG heart/mediastinum ratios: a phantom study. Eur J Nucl Med Mol Imaging. 2005;32:1100-1107.
16. Agostini D, Carrio I, Verberne HJ. How to use myocardial (123)I-MIBG scintigraphy in chronic heart failure. Eur J Nucl Med Mol Imaging. 2008;36:555-559.
17. Kline RC, Swanson DP, Wieland DM, Thrall JH, Gross MD, Pitt B, et al.Myocardial imaging in man with I-123 meta-iodobenzylguanidine. J Nucl Med. 1981;22:129-132.
18. Verberne HJ, Busemann Sokole E, van Moerkerken A, Deeterkink J, Ensing G, Stabin MG, et al. Clinical performance and radiation dosimetry of no-carrier-added vs carrier-added 123I-metaiodobenzylguanidine (MIBG) for the assessment of cardiac sympathetic nerve activity. EurJ Nucl Med Mol Imaging; 35:798-807. 19. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM.Development
and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660-2667. 20. Flack JM, Neaton JD, Daniels B, Esunge P. Ethnicity and renal disease: lessons from the Multiple Risk Factor Intervention Trial and the Treatment of Mild Hypertension Study. Am J Kidney Dis. 1993;21:31-40.
21. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DN, Levey AS, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;38:955-62.
22. Mahon NG, Blackstone EH, Francis GS, Starling RC 3rd, Young JB, Lauer MS. The prognostic value of estimated creatinine clearance alongside functional capacity in ambulatory patients with chronic congestive heart failure. J Am Coll Cardiol. 2002;40:1106-1113.
23. Kearney MT , Fox KA, Lee AJ, Prescott RJ, Shah AM, Baatin PD, Baig W, et al. Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure. J Am Coll Cardiol. 2002;40:1801-8.
24. McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol. 2002;13:1928-36.
25. McAlister FA, Ezekowitz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation. 2004; 109:1004-1009.
26. Agostini D, Verberne HJ, Burchert W, Knuuti J, Povinec P, Sambuceti G, et al. I-123- m IBG myocardial imaging for assessment of risk for a major cardiac event in heart failure patients: insights from a retrospective European multicenter study. Eur J Nucl Med Mol Imaging. 2008; 35:535-46.
27. Opasich C, Tavazzi L, Lucci D, Gorini M, Albanese MC, Cacciatore G, et al.Comparison of one-year outcome in women versus men with chronic congestive heart failure. Am J Cardiol. 2000;86:353-357.
28. Hunt SA, Abraham WT, Chin HM, Feldman AM, Francis GS, Ganiats TG, et al. ACC/ AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154-e235.
29. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442.
